Our broad, long-term objectives are to understand the fundamental properties and operative mechanisms of infectious prion transmission, and ultimately to prevent unpredictable recurrences of prion epidemics. This application focuses on chronic wasting disease (CWD), a burgeoning, highly contagious cervid prion disease which has attained global epidemic status. Understanding the properties of North American, European, and Asian CWD prions is an important goal of this proposal. We propose three Specific Aims to address our central hypothesis: that the conformationally protean properties of CWD prions results in the evolution of strains with novel host range properties, and unpredictable zoonotic potential. Our Lead Aim seeks to characterize the transmission properties of emergent Norwegian and South Korean CWD prions. It builds upon our preliminary findings that the strain properties of Scandinavian and North American CWD prions are distinct. We will comprehensively assess and compare the transmission properties emergent CWD prions from different geographic locations and species using well characterized transgenic and novel gene-targeted mouse models expressing prion protein (PrP) genes from susceptible species. In Aim II, we will assess the conformational properties of novel CWD strains using innovative ELISA approaches and monoclonal antibodies recognizing defined conformational epitopes. We will assess the properties of CWD strains in cell culture models, and using cell free conversion assays. We will define the amplitude and temporal accumulation of various CWD strains in infected mice by titration in susceptible cells. Finally, using transgenic mouse modeling, we will assess the effects of PrP polymorphisms on strain selection and pathogenesis, and address the susceptibility of at risk species. In our final Aim, we will compare the host-range properties, and zoonotic potential of CWD prions. Our preliminary data describing novel Nor-CWD strains, and the possibility of detecting additional emergent CWD strains, provide additional uncertainty as to whether CWD- exposed humans, or species in contact with wild cervids, are at risk for developing novel prion diseases. We will assess a variety of species barriers by challenging conventional transgenic mouse models expressing PrP from various species including cattle, sheep, and humans, with CWD prions. We will also address the role of CWD adaptation in peripheral tissues on the human species barrier.